Highlights from Recent Cancer Literature
Journal: Cancer Research (2018)

Lung squamous cell carcinomas (LSCC) harbor more neutrophils than lung adenocarcinomas (LADC). Developing new genetically engineered mouse models driven by SOX2, Mollaoglu and colleagues reveal that this genetic circuit controls recruitment of neutrophils and that tumor-infiltrating neutrophils drive squamous differentiation of LSCC. They identified antagonism between the transcription factors SOX2, highly expressed in human LSCC, and Nkx2-1, the defining transcription factor in LADC. Overexpression of SOX2 or loss of Nkx2-1 upregulated CXCL5, which recruited neutrophils to both lung tumor types. Interestingly, depletion of neutrophils in the LSCC model inhibited squamous cell differentiation.Expert Commentary: Genetic drivers of lung cancer, rather than histopathological features, control the infiltration of specific types of immune cells. Tumor-infiltrating neutrophils support the squamous histopathology of lung cancer.Mollaoglu G, Jones A, Wait SJ, Mukhopadhyay A, Jeong S, Aya R, et al. The lineage-defining transcription factors SOX2 and NKX2-1 determine lung cancer cell fate and shape the tumor immune environment. Immunity 2018;49:764–779e9. doi: 10.1016/j.immuni.2018.09.020.Treatment of basal cell carcinoma (BCC) with Hedgehog (Hh) pathway inhibitors leads to dramatic responses; however, these responses are often incomplete and residual disease progresses. Using a transgenic mouse model for BCC, Biehs and colleagues demonstrated that following treatment, a quiescent residual tumor remained despite continued Hh pathway inhibition. Residual cells assumed an alternative cell identity distinct from untreated BCC. This cell identity switch was accompanied by Wnt pathway upregulation. Critically, dual inhibition of Hh and Wnt pathways decreased residual disease and delayed recurrence.Expert Commentary: This study identifies novel mechanisms of resistance through transdifferentiation to a cell identity that no longer required the oncogenic driver and suggests a novel therapeutic strategy to overcome resistance.Biehs B, Dijkgraaf GJP, Piskol R, Alicke B, Boumahdi S, Peale F, et al. A cell identity switch allows residual BCC to survive Hedgehog pathway inhibition. Nature 2018;562:429–33.Metabolic reprogramming is an essential component of cancer cell development and progression. Cellular metabolism can be fragmented into modules that represent fundamental metabolic processes. Cubuk and colleagues modified metabolic gene expression modules so that each module focused on only one metabolite. This resulted in 95 metabolic gene expression modules, whose alterations serve as a proxy for changes in metabolism. Examination of modules across 10,000 samples from 25 distinct types of cancer identified modules correlating with outcome, as well as potential new therapeutic targets within these modules. They validated their findings using public datasets as well as by knockdown of a key regulator of pyrimidine degradation that they discovered, resulting in selective growth inhibition of two gastric cancer cell lines.Expert Commentary: This work develops and validates a series of metabolic gene expression modules, which will allow metabolic changes to be more easily monitored for prognostic or diagnostic purposes.Cubuk C, Hidalgo MR, Amadoz A, Pujana MA, Mateo F, Herranz C, et al. Gene expression integration into pathway modules reveals a pan-cancer metabolic landscape. Cancer Res 2018;78:6059–72.Post-transcriptional regulatory pathways have been implicated in breast cancer progression. Fish and colleagues carried out small RNA sequencing of breast cancer cell lines and patient-derived xenograft models. Coupled with analysis of clinical breast cancer datasets, this study identified breast cancer-specific small orphan noncoding RNAs (oncRNA). One such oncRNA, named T3p, was associated with breast cancer progression and drove metastases in mouse models by regulating expression of prometastatic genes NUPR1 and PANX2. Mechanistically, T3p regulated gene expression by inhibiting activity of the RISC complex. Interestingly, oncRNAs were found in extracellular vesicles from sera of patients with breast cancer but not from healthy volunteers.Expert Commentary: The tumor-specific generation of oncRNAs provides a new post-transcriptional regulatory pathway governing tumor progression. Furthermore, oncRNA profiling in serum samples has the potential to be a powerful diagnostic tool.Fish L, Zhang S, Yu JX, Culbertson B, Zhou AY, Gog A, et al. Cancer cells exploit an orphan RNA to drive metastatic progression. Nat Med 2018;24:1743–51.Oncogenic Kras drives over 90% of pancreatic ductal adenocarcinoma (PDAC). PIN1 is a key effector molecule in the Kras/ERK axis. Liang and colleagues elucidated effects of PIN1 on redox homeostasis in Kras-driven PDAC. The authors demonstrate that PIN1 was widely upregulated in Kras-mutant PDAC, correlating inversely with outcome. Genetic targeting of PIN1 impaired Kras-directed proliferation and tumorigenesis. Moreover, PIN1 maintained redox balance via synergistic activation of c-Myc and NRF2, upregulating expression of antioxidant response element (ARE)-driven genes in PDAC cells.Expert Commentary: This study identifies PIN1 as a prominent regulator of redox homeostasis for cell survival via cooperation with the c-Myc/NRF2/ARE axis, suggesting PIN1 as a focal target for the treatment of Kras-driven pancreatic cancer.Liang C, Shi S, Liu M, Qin Y, Meng Q, Hua J, et al. PIN1 maintains redox balance via the c-Myc/NRF2 axis to counteract Kras-induced mitochondrial respiratory injury in pancreatic cancer cells. Cancer Research; Published first October 24, 2018; doi: 10.1158/0008-5472.CAN-18-1968.N6-methyloadenosine (m6A) mRNA modification is catalyzed by the methyltransferase-like 3 enzyme (METTL3). Choe and colleagues report that METTL3 enhances translation only when tethered to mRNA close to the stop codon. METTL3 binds to polyribosomes near 5′ cap-binding proteins. Moreover, METTL3 directly interacts with the translation initiation factor eIF3h through mRNA circularization, promoting translation of oncogenic mRNAs, including BRD4. Depletion of METTL3 reduced expression of BRD4 in lung cancer cells, increased sensitivity to BRD4 inhibition, and suppressed growth of xenografts. Ectopic expression of METTL3 promoted invasion and tumor growth. These results demonstrate that the METTL3-eIF3h interaction enhances mRNA looping and thereby facilitates oncogenic translation to drive tumorigenesis.Expert Commentary: This study demonstrates how METTL3-mediated m6A modification regulates the translation of oncogenic mRNAs, adding to evidence suggesting METTL3 or the METTL3-eIF3h interaction as targets in cancer.Choe J, Lin S, Zhang W, Liu Q, Wang L, Ramirez-Moya J, et al. mRNA circularization by METTL3-eIF3h enhances translation and promotes oncogenesis. Nature 2018;561:556–60.Note: Breaking Insights are written by Cancer Research editors. Readers are encouraged to consult the articles referred to in each item for full details on the findings described.